WO2021087055A1 - Imagerie optique et de résonance magnétique 13c à double mode, et contraste élevé utilisant des particules de diamant - Google Patents

Imagerie optique et de résonance magnétique 13c à double mode, et contraste élevé utilisant des particules de diamant Download PDF

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WO2021087055A1
WO2021087055A1 PCT/US2020/057874 US2020057874W WO2021087055A1 WO 2021087055 A1 WO2021087055 A1 WO 2021087055A1 US 2020057874 W US2020057874 W US 2020057874W WO 2021087055 A1 WO2021087055 A1 WO 2021087055A1
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diamond particles
imaging
image
hyperpolarized
target
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Jeffrey A. REIMER
Alexander Pines
Ashok Ajoy
Xudong Lv
Olga Shenderova
Marco Diego TORELLI
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The Regents Of The University Of California
Adamas Nanotechnologies
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0033—Features or image-related aspects of imaging apparatus classified in A61B5/00, e.g. for MRI, optical tomography or impedance tomography apparatus; arrangements of imaging apparatus in a room
    • A61B5/0035—Features or image-related aspects of imaging apparatus classified in A61B5/00, e.g. for MRI, optical tomography or impedance tomography apparatus; arrangements of imaging apparatus in a room adapted for acquisition of images from more than one imaging mode, e.g. combining MRI and optical tomography
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
    • A61B5/0071—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence by measuring fluorescence emission
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/05—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves 
    • A61B5/055—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves  involving electronic [EMR] or nuclear [NMR] magnetic resonance, e.g. magnetic resonance imaging
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
    • A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
    • A61K49/0089—Particulate, powder, adsorbate, bead, sphere
    • A61K49/0091—Microparticle, microcapsule, microbubble, microsphere, microbead, i.e. having a size or diameter higher or equal to 1 micrometer
    • A61K49/0093—Nanoparticle, nanocapsule, nanobubble, nanosphere, nanobead, i.e. having a size or diameter smaller than 1 micrometer, e.g. polymeric nanoparticle
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
    • A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
    • A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
    • A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
    • A61K49/1875—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle coated or functionalised with an antibody
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54313—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being characterised by its particulate form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B1/00—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor
    • A61B1/04—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor combined with photographic or television appliances
    • A61B1/043—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor combined with photographic or television appliances for fluorescence imaging

Definitions

  • MRI and optical imaging offer diametrically complementary advantages, a feature that can make them particularly powerful in combination. Visible-wavelength optics is fast, cheap and images at high-resolution; yet often suffers from scattering, attenuation, and aberration distortion when imaging through tissue.
  • MRI on the other hand, is noninvasive, fully three-dimensional and can be chemically functional; yet it is slow, suffers from weak signals, and offers poor spatial (mm-level) resolution.
  • optical and MR imaging are carried out in Fourier- reciprocal spaces (x- and k-space). This redundancy immediately makes a combined modality highly persuasive.
  • Figure 1 A shows an embodiment of a dual -mode imaging apparatus.
  • Figure IB shows a graphical representation of the hyperpolarization protocol and detection.
  • Figure 1C shows a signal gain from a dual -mode imaging process.
  • Figure ID shows an embodiment of a phantom ring filled with diamond particles used for dual-mode imaging.
  • Figure IE shows an embodiment of a phantom ring captured with optical imaging.
  • Figure IF shows an embodiment of a phantom ring captured with magnetic resonance imaging.
  • Figure 2A shows a graphical representation of a normalized fluorescence signal for randomly oriented ensemble of diamond particles under an applied magnetic field.
  • Figure 2B shows signal contrast for optical modulation under a pulsed magnetic field.
  • Figure 2C shows optical images captured when diamond particles were under a magnetic field.
  • Figure 2D shows examples of magnetic resonance images under opposite microwave field sweeps.
  • Figure 2E shows a graphical representation of the result of a positive magnetic field sweep and a negative microwave field sweeps.
  • Figures 3A-B show a graphical representation of an imaging die.
  • Figures 3C-D show examples of magnetic resonance and optical images with a strong artificial background.
  • Figures 3E-F show examples of magnetic resonance and optical images with the background suppressed.
  • Figures 4A-B shows an embodiment of a process of accelerated imaging with accompanying images.
  • Figure 4C shows a graph of sampling width versus normalized time versus acceleration.
  • Figure 4D shows a graph of scaling of optimal sampling sizes with scarcity.
  • Figure 4E shows a graph of optimized imaging acceleration through sampling of an optimal number of points.
  • Figure 4F shows a graph of a trajectory of convergence between two images.
  • Figure 5 shows a schematics of the correlative MRI/optical colonoscopy using targeting fluorescent nanodiamond probes with 13 C optically hyperpolarized at room temperature.
  • Figure 6 shows a schematics of a method of dual mode imaging using hyperpolarized diamond particles.
  • dual mode imaging means high contrast dual-mode optical and 13 C MRI imaging in diamond microparticles.
  • These versatile materials have gained prominence for tumor targeting given their biocompatiblity and surface functionalizability with antibodies, dendrimers and other targeting ligands.
  • the diamond particles are incorporated with a large concentration (approximately > 1 ppm) of Nitrogen Vacancy (NV) defect centers.
  • NV Nitrogen Vacancy
  • the particles fluoresce brightly in the red with high luminosity ( ⁇ 90 cd/m 2 ), with high optical stability, without blinking or bleaching.
  • the NV centers are also endowed with attractive spin properties.
  • the generation of fluorescence occurs concurrently with the optical polarization of the electron spins associated with them.
  • This macroscopically large polarization >10%) can be transferred to 13 C nuclei in the surrounding lattice, hyperpolarizing them in vastly athermal states that bequeath them with brightness in MR imaging.
  • the embodiments here exploit a recent NV-mediated low- field (1-70 mT) room-temperature hyperpolarization technique that allows large 13 C polarization levels ( ⁇ 1%) and correspondingly high MR signal enhancement factors, over a factor of thousand at 1.5 T.
  • the embodiments demonstrate high contrast optical and MRI imaging in phantom samples, and show suppression of signal backgrounds by over factors of 2 and 5 respectively in the two imaging dimensions respectively.
  • the embodiments demonstrate how combined conjugate imaging in real and k-space can promote several orders of magnitudes in imaging acceleration, particularly in wide field-of-view scenarios. This work paves the way for high contrast, background-free, accelerated dual-mode imaging of biocompatible nanoparticle delivery and targeting agents based on quantum materials.
  • Fig. 1A shows a schematic of one embodiment of the experiment.
  • Diamond particles such as 10 (200 pm, ⁇ 40 mg) arranged in a ring-shaped phantom, as shown in Fig. ID, are imaged optically under continuous 520 nm illumination from the laser 12 and 630 nm long- pass filtering, as shown in Fig. IE.
  • the high intrinsic SNR from the optical florescence is evident, and the ultimate imaging resolution is just diffraction limited.
  • the process employs dynamic nuclear polarization (DNP) at 38 mT 14 to enhance the 13 C polarization, and a microcoil 16 in a 9.4 T magnet for imaging.
  • DNP dynamic nuclear polarization
  • One embodiment uses a variant of FLASH (fast low angle shot MRI) to produce the MRI images at 9.4 T as can be seen in Fig. 1F.
  • FLASH fast low angle shot MRI
  • the width of the radio frequency (RF) pulses and the gradient lobes are minimized to create a short echo time (0.5 ms).
  • the imaging was performed without a slice selection gradient as shown in Fig. IB. This is also possible since the primary interest lies in projection images along the z-axis.
  • the SNR of the MR image shown in Fig. IF is ⁇ 4 in 16 scans, limited by rapid 13 C T2 decay, low sample filling factor ( ⁇ 0.0016) and laser-limited hyperpolarization.
  • the use of line-narrowing sequences, such as spin-locking or quadratic echoes, can improve the imaging SNR by at least an order of magnitude.
  • the use of higher laser power close to saturation intensity ( ⁇ 1 W/mm3) can increase the MR signal 10 times compared with the present results. Diamonds with higher 13 C content will provide larger signals, with the resulting SNR improvement scaling with enrichment.
  • the MRI spatial resolution scales a 1 /yG max ⁇ ), where g is the gyromagnetic ratio, G max and ⁇ are the maximum gradient strength and the duration of its application.
  • Gmax 950 mT/m, leading to a resolution of 640 pm in both dimensions.
  • the pixel size presented in the image shown in Fig. IF has a square length of 160 pm.
  • Recent amplifier development that increase Gmax can improve the spatial resolution.
  • the MR resolution can be just optical diffraction- limited, since only illuminated diamond particles contribute to any signal.
  • beam-rastering modalities that buildup MR images pixel-by-pixel, in a manner that is solely resolution limited by optics.
  • the optical DNP method discussed here presents several advantages when compared with traditional methods of hyperpolarization for solids imaging, employed for instance in 29 Si microparticles.
  • the process works at room temperature and low field ( ⁇ 40 mT), and polarize samples in under 1 minute of laser pumping, as opposed to traditional high magnetic field (approximately > 3T) and low temperature ( ⁇ 4K) approaches where polarization buildup can take several hours. While the absolute polarization is lower in the methods here, they circumvent the traditionally high polarization loss, which can be as large as 99%, accrued upon thawing and sample transfer out of the cryostat; ultimately, this results in a relatively high level of polarization delivery at the imaging source.
  • the techniques here aid end-user operation.
  • the MW amplifiers and sweep sources are low-cost and readily available, empowering the construction of highly portable hyperpolarization devices that can retrofit to existing MRI scanners.
  • the embodiments here would open possibilities for continuous low-field MRI, along with simultaneous optical imaging in-situ, particularly attractive because the hyperpolarization can be replenished optically.
  • Both optical and MRI modalities allow on-demand signal amplitude modulation, enabling common-mode suppression of background signals in both imaging dimensions.
  • the embodiments simulated the fluorescence dependence under application of B ext , shown in Fig.
  • MRI amplitude modulation relies on the remarkable dependence of the 13 C hyperpolarization sign on the direction of MW sweeps, a feature originating in the rotating frame LZ dynamics excited by the chirped microwaves as shown in Fig. 2E.
  • the 13 C nuclei are aligned with the polarization field under low-to-high frequency sweeps, or anti-aligned with the high to low frequency sweeps, over the NV ESR spectrum.
  • this allows a complete sign-reversal of the MRI images at full contrast, all while requiring no additional infrastructure.
  • it is challenging to achieve such high signal modulation contrasts with conventional cryogenic DNP approaches primarily due to technical limitations of MW cavity switching in these experiments.
  • Such high-contrast signal modulation opens the door to imaging the diamond particles with high SNR even while embedded in an overwhelmingly strong background.
  • background in this context refers to media that have fluorescence or 13 C NMR signals that overlap in wavelength, or NMR frequency, with the diamond particles.
  • the process used particles being co-included with a high concentration of Alexa 647, a fluorescence dye which has a strong emission at 600 nm, as well as [ 13 C] -methanol, which has a chemical shift nearly overlapping that of diamond.
  • These solution media fill both the inner and outer spaces of the capillary tube that comprise the diamond phantom in Figs. 3A- B.
  • the strong backgrounds result in images that are circle-shaped since the diamond phantom is completely indiscernible within it as shown in Fig. 3C-D.
  • hyperpolarization sign control allows one to address the diamond 13 C nuclei in exclusion of all other 13 C spins in the sample.
  • MR imaging can become preeminent even for buried particles relatively shallow in depth. If h were to be the ratio of optical and MR imaging SNR for surface diamond particles, MR imaging would have higher overall SNR than its optical counterpart at a depth d ⁇ — log( ⁇ ) mm at 650nm, scaling logarithmically with the differential SNR ratio. Importantly, since both optical and MR imaging can proceed simultaneously, there are opportunities to use a “maximum-likelihood” hybrid of both modalities, wherein MR gains prominence with increasing depth profile.
  • Fig. 4A describes one such imaging protocol. Given a sparse original image to be acquired, a subset l k-space points are first sampled in each dimension. The resulting blurry low-k image is thresholded and fed-forward to confine real-space points to be sampled through optical means. At high sparsity s, defined here as the fraction of zero pixels in the FOV, this can substantially reduce the number of points in real-space to be rastered over, and accelerate image acquisition.
  • FIG. 4C where, in a 32 x 32 pixel FOV, one can see the normalized imaging time savings over either modality for target images with varying sparsity.
  • the process performed a statistical analysis with 30 image configurations of fixed sparsity, assuming that the minimum feature size occupies one pixel.
  • Fig. 4C demonstrates that hybrid sampling can deliver more than an order of magnitude in time savings (right axis), while only requiring the scanning of l 0pt ⁇ 10% of total k-space (upper axis), notwithstanding the relatively small FOV considered.
  • l opt increases with decreasing sparsity, a reflection of larger k-samples required to account for the increasing image complexity, see Fig. 4D.
  • Fig. 4E shows the combined imaging time t under optimized conditions as a function of image sparsity, assuming that time for optical imaging is 1. Indeed, the imaging acceleration is quite substantial, scaling as T 1 ⁇ (1 s) -1/2 , and becoming increasingly utilitarian at high image sparsity.
  • C ⁇ (l — (/)) (/' — (/')) where ( ⁇ ) indicates the mean value.
  • N object of pixel radius r is effectively blurred where the factor ro is set by the thresholding level employed, and l/N is the effective k-space sampling ratio.
  • the k- space imaging constrains the area required for subsequent optical scanning to just this blurred region; increasing l makes a more faithful representation and improves regional constraints, but comes is associated with a time-cost.
  • the embodiments here have demonstrated a new means of dual-mode imaging in diamond microparticles, and shown that a slew of complimentary advantages can be harnessed by marrying together visible optical and 13 C MR imaging.
  • the biocompatible particles employed have a high density of NV defect centers.
  • the same optical excitation that causes high-luminosity visible fluorescence from the NVs also serves to spin-polarize the lattice 13 C nuclei making the particles light up in MR imaging.
  • the embodiments demonstrated MR signal enhancements by -204 over 9.4 T under weak (-80 mW/mm 2 ) optical illumination, and simultaneously bright optical florescence.
  • imaging in optical and MRI domains inherently occurs in Fourier- conjugate spaces, and allows development of hybrid protocols that feed-forward information from one domain to another to vastly accelerate image acquisition.
  • the potential to accelerate image acquisition by about two orders of magnitude has been demonstrated.
  • the high surface area diamond particles present an attractive platform through which the hyperpolarization could be transferred out into the targeting groups, including but not limited to antibodies, cellular receptors, proteins, DNA, drug molecules, metabolites, pyruvate, free radicals, intracellular components, cellular membranes, extracellular components and other biological substances potentially making them chemically-functional dual-mode imaging agents. Hyperpolarization transfer from diamond particles can be also considered for the targeting groups comprising non-biological substance.
  • the optical imaging is performed under simultaneous excitation from four 520 nm fiber-coupled laser diodes (Lasertack) in a rhomboidal configuration, and the florescence imaged on a CMOS detector (Thorlabs DCC1645C) through a 594 nm long pass filter (Semrock BLP01-594R-25).
  • the hyperpolarization apparatus contains laser excitation, microwave irradiation and weak electro-magnet to fine-tune the polarization field.
  • the embodiments employ a miniature 1W 520 nm diode laser (Lasertack PD-01289) in a feedback loop with an integrated thermoelectric cooler for adequate thermal control (TE Inc. TE- 63-1.0-1.3).
  • Frequency sweeps are produced by controlling the VCO frequency by a homebuilt quad channel voltage ramp generator controlled by a PIC microprocessor (PIC30F2020).
  • the sweep generator employs dual multiplying digital-to- analog convertors (MDACs, Linear Technology LTC1590) to generate the sawtooth voltage ramps. All MR images are taken with the particles immersed in water or solution.
  • a pneumatic field-cycling device was implement to enable rapid sample transfer from low field (40 mT) to high a wide-bore 9.4 T Bruker DRX MRI machine, within which a 10 mm 1H/ 13 C Volume Coil is installed.
  • the shuttling device is composed of a quartz channel transporting the sample, a concave-shape stopper at the end of the channel, and driven by a vacuum machine to transfer the sample in under Is.
  • Dual-mode imaging technology using hyperpolarized fluorescent diamond particles is particularly useful in clinical settings involving endoscopic imaging, including but not limited to the screening, surveillance, maintenance, or management of colorectal cancer (CRC), bladder cancer, gastro-Intestinal (GI) cancer, and other pathologies where endoscopy is applicable.
  • Other clinical settings where the dual-mode imaging can be of particular use include but are not limited to prostate cancer, sentinel lymph node detection, image-guided surgery, and detection and maintenance of skin cancer. In these setting depths of light penetration through tissue allows for hyperpolarization of diamond particles incorporated into the tissue and body fluids.
  • Yet other targets for visualization using hyperpolarized diamond particles comprise blood clots, thrombi, including their degradation products, as well as other cardiovascular malignancies.
  • the method of imaging using hyperpolarized diamond particles also include targets for visualization such as at least one of a stent, needle, biopsy needle, catheter, implant, where diamond particles can be incorporated into coatings of the medical devices and provide their visualization in a body using MRI or MRI/optical dual-mode imaging.
  • targets for visualization such as at least one of a stent, needle, biopsy needle, catheter, implant, where diamond particles can be incorporated into coatings of the medical devices and provide their visualization in a body using MRI or MRI/optical dual-mode imaging.
  • MRI/optical dual mode imaging for colon examination.
  • Colonoscopy is the gold standard to reduce risk by detection of both premalignant neoplasms and carcinomas.
  • 86% of all post-colonoscopy CRC can be explained by missed lesions which could have been prevented.
  • targeted-fluorescence imaging could improve detection accuracy by generating cancer-specific contrast not possible in standard white-light endoscopy, the colon’s geometric complexity is an encumbrance which limits optical detection.
  • the use of MRI to inform the endoscopist pre- or intraoperatively could greatly reduce miss rates; however, sensitivity is not enough to detect small lesions.
  • the dualmode imaging technology of the present invention based on safe targeting diamond particles contrast agents endowed with bright fluorescence and strong nuclear magnetic resonance 13 C signatures can significantly increase fidelity of the detection and improve the detection rate of precancerous and cancerous lesions in colorectal cancer. Leveraging the MRI and optical detection of labeled malignances during colonoscopy, performed either sequentially or concurrently, could greatly improve the sensitivity of lesion detection.
  • MRI provides a map of the lesion distribution within the colon informing the correlated optical examination, while fluorescence-guided colonoscopy highlights lesions on the colon surface to facilitate adenoma removal and biopsy as currently practiced and example of which is shown in Fig. 5. [0065] In Fig.
  • the hyperpolarized diamond particles 20 have been attached to a targeting ligand 22. These are then inserted or otherwise placed into the body where a malignant lesion such as 24 may exist.
  • the contrast regions such as 26 result from the diamond particles seen by the MRI, in the MRI image of the colon 28.
  • the luminescence within the colon is seen at 30, with the hyperpolarizing device 32 allowing optical imaging of the diamond particles, seen in fluorescence imaging 34.
  • Dual-mode MRI/fluorescence endoscopy allows imaging across multiple length scales, with potentially cellular level resolution optically and organ-level information via MRI as shown in Fig. 5.
  • the dual mode imaging technology couples fluorescence colonoscopy and low field MRI respectively comprising two essential components: targeting of cancer ous/precancerous tissue in the colon with the fluorescent contrast reagent and the technique of the in vivo reagent hyperpolarization, where a simple optical fiber and a low power microwave source fitted on the endoscope would serve to illuminate these particles in vivo, enabling their imaging directly optically through the endoscope, as well as through low-field MRI.
  • One embodiment involves method of dual mode imaging using hyperpolarized diamond particles as shown in Fig. 6.
  • the process provides diamond particles with enhanced hyperpolarizability.
  • These diamond particles then have targeting ligands attached to them at 102.
  • the ligands may be selected based upon their ability to increase cellular uptake of the diamond articles.
  • the process then attaches the diamond particles with the attached ligands to a target at 104 and removes unbound particles at 106.
  • the diamond particles then undergo hyperpolarization at 108 by application of a specific sequence of microwaves and magnetic field while being illuminated with light.
  • the process then images the target with attached hyperpolarized diamond particles using a magnetic resonance imager at 110, while also imaging the target using fluorescence imager at 112, although these processes do not have to occur simultaneously.
  • the images from the MIR and the fluorescent imager undergo correlation at 114, resulting in a combined image.
  • the process of hyperpolarization at 108 through the correlation at 114 may be repeated as necessary as shown at 116.
  • control particles are particles emitting another fluorescent color but have not targeting ligands attached, but are administered at similar concentrations as targeting particles, those having ligands attached. If no tumor is present, particles of both colors will be randomly distributed in a similar manner. If problematic tissue is present, a significant excess of the targeting particles will attach to the cancer lesions over the non-targeting particles of the other color.
  • the diamond particles hyperpolarization may occur using an endoscope while imaged in a MR imager only, as discussed above.
  • the target is at least one of cancerous lesion, cancerous cell, cancerous tissue, pre-cancerous lesion, neoplastic lesion, cell receptors, cancer markers, colorectal cancer, bladder cancer, GI cancer, prostate cancer, sentinel lymph node, cancer containing target in image guided surgery; skin cancer.
  • the presence of a target confirmed in both MR imaging and fluorescence imaging increases the fidelity of a conclusion of the target’s presence and size.
  • One embodiment may include a method of imaging using hyperpolarized diamond particles comprises particles with size varied between about 10 nm and about 10 um; and where upon hyperpolarization the NMR signal enhancement varies between 0.1 and 20000 at 7 T.
  • the diamond particles with enhanced hyperpolarization can contain NV centers in the concentration between approximately 1 ppm and 10 ppm.
  • the hyperpolarized diamond particles provide fluorescence emission in at least one of NIR, red, green, blue, and UV spectral ranges and where illumination of the diamond particles with light comprises at least one of NIR, red, green, blue and UV spectral ranges, and the blue and green spectral ranges.
  • the attachment of the targeting ligands is done by chemical conjugation of at least one of an antibody, protein, peptide, molecule, folic acid, carbohydrate, or nucleic acid.
  • An example of a targeted biomarker for CRC screening comprises epithelial growth factor receptor (EGFR), which is overexpressed in carcinomas.
  • Targeting can be performed by conjugation fluorescent diamond particles (FDP) with approved antibodies, such as cetuximab and panitumumab.
  • FDP conjugation fluorescent diamond particles
  • One embodiment includes diamond particles functionalized with poly(glycerol) by ring opening polymerization in neat glycidol to introduce colloidal stability in biological media followed by conjugation to cetuximab by carbodiimide or related activation.
  • cetuximab fragments or other anti-EGFR antibodies with a stronger binding constant can be used.
  • biological compatible excipients can be used to stabilize the colloid including serum albumin and trehalose.
  • targets of CRC comprise carcinoembryonic antigen, vascular endothelial growth factor A (VEGFA), or Integrin anb3.
  • One embodiment includes a method of imaging using hyperpolarized diamond particles comprises administering the diamond particles with the targeting ligands to a target comprising at least one of instilling with fluid into a body cavity; intravenous injection; locally; orally; systemically; intramuscular injection; intravascular injection; and intranasally.
  • the removing of unbound diamond particles including but are not limiting to CRC imaging comprises instilling body cavities with liquid, removing liquid and repeating the process at least once.
  • the unbound particles can be removed by a flow of body fluids.
  • Another embodiment includes the method of imaging using hyperpolarized diamond particles, where the hyperpolarization procedure comprises excitation with light from the spectral range of about 450 nm to 600 nm, preferably with excitation from 500 nm to 570 nm, and power between 1 mW and 100 mW; use of microwaves at frequency 0 - 100 GHz and power 1 mW-100 W; and magnetic field 1 mT to 3 T.
  • the source of light, microwaves and magnetic field can be a part of a hyperpolarization device with dimensions and geometry suitable for insertion into at least one of a body cavity, tissue, organ and body fluid system.
  • the hyperpolarization device comprises at least one of an endoscope, a colonoscope, acystoscope, and a laparoscope. In another embodiment it can be a free standing device.
  • Fluorescence imaging of a target with attached hyperpolarized diamond particles using fluorescence imager comprises using optical fibers inserted into at least one of a body cavity, tissue, organ and a body fluid, where imaging of the target with attached hyperpolarized diamond particles further comprises collection of fluorescence images taken in the presence and absence of a magnetic field and further comprises the images subtraction and producing a background free image of the target.
  • Another embodiment includes the method of imaging using hyperpolarized diamond particles, where imaging the target with attached hyperpolarized diamond particles using a magnetic resonance imager comprises low field MR imager; high field MR imager; NMR spectroscope; image modulation; image subtraction and lock-in procedure.

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Abstract

La présente invention concerne un procédé d'imagerie bi-mode de particules de diamant hyperpolarisées comprenant la fixation des particules de diamant à un objet, l'application d'une séquence de micro-ondes et d'un champ magnétique aux particules de diamant tout en éclairant les particules de diamant avec de la lumière pour produire des particules de diamant hyperpolarisées, la capture d'une image de résonance magnétique des particules de diamant hyperpolarisées, la capture d'une image optique des particules de diamant hyperpolarisées, et la corrélation de l'image de résonance magnétique à l'image optique pour produire une image bi-mode. Un procédé d'imagerie utilisant les particules de diamant hyperpolarisées comprend la fourniture de particules de diamant ayant une hyperpolarisabilité renforcée, la fixation des ligands de ciblage aux particules de diamant, l'administration des particules de diamant aux ligands de ciblage à une cible fournissant une pluralité des particules de diamant fixées à la cible, l'élimination des particules de diamant non liées, l'éclairage des particules de diamant avec de la lumière tout en appliquant simultanément une séquence spécifique de micro-ondes et un champ magnétique induisant l'hyperpolarisation des particules, et l'imagerie de la cible avec des particules de diamant hyperpolarisées fixées en utilisant un imageur à résonance magnétique pour obtenir une image de résonance magnétique.
PCT/US2020/057874 2019-10-30 2020-10-29 Imagerie optique et de résonance magnétique 13c à double mode, et contraste élevé utilisant des particules de diamant WO2021087055A1 (fr)

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